The participation of the C3 protein in immune surveillance and immune response pathways has been well documented; however, information concerning the structural correlates of its biological activities has not been forthcoming. Activation of the complement system by the "classical" or "alternative" pathways results in a selective and controlled fragmentation of the C3 molecule. Interactions of C3 fragments with surface receptors of the PMN, B-cell, and monocyte serve to modulate complement-dependent granulocyte and lymphocyte functions. The elucidation of molecular features germane to these membrane directed complement functions will require (1) further characterization of the structures of the individual complement proteins involved, and (2) an evaluation of the physicochemical basis for their binding properties. We intend to meet both of these requirements in our studies. The isolation of major activation fragments and subsequent chemical analysis will contribute to further structural delineation of the C3 molecule. Once the cleavage fragments of C3 with cell binding activities have been identifed, specific peptide inhibition experiments should establish subregions of these ligands that constitute receptor binding sites. If such oligopeptides can be obtained, they may have specific application as inhibitors of in vivo C3:C3 receptor interactions. Therefore, this approach has the potential of offering a new class of inhibitors to the processes involved in inflammatory reactions, especially in the class of autoimmune disorders. Dr. Richard Harrison and I have between us 10 years of independent research experience relating to structural and functional studies of human C3. We now have the unique opportunity at Children's to combine our efforts and work towards solving the complete primary structure of this important protein.